The present invention relates to a new class of cyclic ether derivatives and inner salts and pharmaceutically acceptable salts thereof which have excellent antagonism against platelet activating factor (hereafter abbreviated, as is conventional, to "PAF").
Natural PAF, at least as isolated from mammalian tissues, is a mixture of from 2 to 5 phospholipids, the number depending upon the nature of the original tissue. The major constituents of PAF may be represented by the formula (A): ##STR3## in which p is the integer 15 or 17. Natural PAF is levorotatory and the various components of natural PAF may be identified, for example as: l-C.sub.16:0 =formula (A) where p is 15; and l-C.sub.18:0 =formula (A) where p is 17.
PAF exhibits a strong platelet activating and aggregating effect. It also has a hypotensive effect and increases vasopermeability; it is believed to be an active agent in the induction of anaphylactic shock (for example endotoxin-induced shock), to act as a mediator of inflammatory disease and to act as an activator of neutrophiles. Accordingly, PAF antagonists have been investigated with a view to developing new types of anti-shock agent and of anti-inflammatory agent. In particular, analogs of natural PAF's have been investigated in an attempt to find such PAF antagonists. Currently, several compounds are known as PAF antagonists. For example, the compound of formula (B): ##STR4## (also known as CV-3988) is disclosed in U.S. Pat. No. 4,408,052, whilst the compound of formula (C): ##STR5## (known as ONO-6240) is disclosed in European Patent Publication No. 146258. These compounds however, are unsatisfactory for one or more of the following reasons: they lack sufficient intensity of antagonism towards PAF; the duration of their effect is insufficient; biological utilization is inadequate.
The closest prior art, from the structural point of view, to the compounds of the present invention is believed to be the compounds disclosed in U.S. patent application Ser. No. 818 876 filed 14th Jan. 1986. However, these prior compounds are useful as anti-tumor agents, and appear to be substantially free from PAF-like activity and from PAF antagonistic activity. On the contrary, the compounds of the present invention have been found to be excellent PAF antagonists, resulting in anti-asthmatic, anti-inflammatory and anti-shock activities which have excellent duration, biological utilization and level of activity. Other PAF antagonists are described in U.S. patent application Ser. No. 014 936 filed 13 Feb. 1987, but those compounds, unlike those of the present invention, lack a cyclic ether structure.
Other glycerol derivatives known to have PAF inhibitory activity are disclosed in EP Patent Publication No. 157 609.